Cancer is a general term used when referring to any disease state that results from an abnormal uncontrolled and progressive cellular growth. There are presently three major methods available for the treatment of cancer. These methods are surgery, radiotherapy and chemotherapy. Each method of treatment may be effective by itself; however, when administered in combination, the results are frequently more favorable. A common example of such a combination would be the utilization of surgery to remove a tumor followed by treatment with certain chemicals capable of controlling or eliminating remaining cells which may move through the body to seed the growth of additional tumor sites (metastasis).
Unfortunately, such treatment with chemicals (chemotherapy) continues to have very serious disadvantages. In particular, none of the approximately 30 drugs commonly used in cancer chemotherapy have proven to be capable of eliminating the cancer disease except in a relatively small number of isolated cases. Furthermore, most of these chemicals have very high toxicity or serious side effects relative to the dosage required to be effective against the abnormal tumor or growth (neoplasm). The use of such chemicals in chemotherapy therefore very often results in serious complications which endanger the human being or other host organism being treated. These disadvantages of cancer treating chemicals (antineoplastic drugs) continue despite the fact that many thousands of potential antineoplastic agents have been screened and tested.
Many of the effective antineoplastic agents are classified as alkylating agents, i.e. a substance which introduces an alkyl, or substituted alkyl radical into a compound in place of a hydrogen atom. In chemicals utilized for treating cancer such alkylation frequently occurs within a nucleic acid structure such as DNA or RNA of the cancer cell thus effectively preventing the cell from functioning or reproducing.
A number of such alkylating agents contain one or more aziridine rings or contain intermediate structures which can yield aziridine rings. An aziridine ring is a three-membered heterocyclic ring containing one nitrogen atom and two carbon atoms. Examples of alkylating chemicals which contain aziridine rings or contain structures which can yield aziridine rings are as follows: ##STR3## These compounds are believed to open at the aziridine ring site, if not already opened at that site, and then combine with a nucleic acid to interrupt the replication of the nucleic acid or to interfere with messages which would be transmitted by the nucleic acid.
In addition to the thio-TEPA and TEPA compounds, numerous other phosphoaziridines are known. Phosphoaziridines are described in numerous publications, for example, in U.S. Pat. No. 3,201,313; by Bardos et al in the Journal of Surgical Oncology 3(4): 431-441 (1971); by Kimler et al in Radiology, 133: pp 515-517 (1979); by Bardos et al in the International Journal of Radiation Oncology Biological Physics, Volume 5: pp 1653-1656 (1979); by Wampler et al in International Journal of Radiation Oncology Biological Physics, Volume 5: pp 1681-1683 (1979); and by Chmielewicz et al in the Journal of Pharmaceutical Sciences, Volume 56, No. 9: pp 1179-1181 (1967).
Initially, phosphoaziridines were considered and classified as alkylating agents. Such phosphoaziridines were later chemically combined through an amide linkage to ethyl carbamate in an attempt to obtain a synergistic effect between the phosphoaziridine and urethane group. The compound and many of its analogues demonstrate potent anti-tumor activity but showed no significant clinical advantage over other alkylating agents.
Bis(2,2-dimethyl-1-aziridinyl)phosphinates were subsequently developed which showed the interesting characteristic of not only being chemicals suitable for chemotherapy but demonstrated the ability to potentiate the therapeutic effects of radiation upon transplanted tumors. The Bis(2,2-dimethyl-1-aziridinyl)phosphinates which were connected with urethane groups or ester groups nevertheless show highly effective anti-tumor activity with remarkably low toxicity for inhibiting the production and development of blood cells (hematopoietic toxicity) when compared with conventional alkylating agents.
The radiation potentiating effect of the (2,2-dimethyl-1-aziridinyl)phosphinates is believed to operate by blocking repair of nucleic acid damaged by radiation; whereas, most other known radiation sensitizing compounds for hypoxic (anaerobic) tumors are believed to operate by increasing initial radiation damage to nucleic acids of the tumor. A useful group of such other known radio sensitizers are members of the "electron affinic" class of sensitizers. The structures of several of such known "electron affinic" anti-tumor radio sensitizers are shown below.
"Phosphoaziridines" as used herein include compounds wherein one to three aziridine rings are attached to a phosphorous atom and two valences of the phosphorous atom are connected to an oxygen or sulfur atom. ##STR4## Unfortunately, such electron affinic compounds which increase the radiation effect upon tumors are usually high neurotoxic.